Transplante de microbioma mediante píldoras

Microbiome transplantation- From : Nature

Patients with a stubborn, debilitating bacterial infection may soon be treated with pills full of microbes derived from human faeces.

Clostridium difficile is a bacterial infection that causes diarrhoea and fever in around half a million people in the United States each year, and is linked to the death of some 14,000 US citizens annually. Some physicians now treat recurrent C. difficile infections with faecal transplants, delivering donor faeces filled with healthy microbes via enemas, colonoscopies or nasal tubes that run directly to the gut.

But capsules containing the same donor bacteria are also effective at giving these ‘gut microbiome transplants’, according to results presented on 3 October at a meeting in San Francisco, California.

Thomas Louie, an infectious-disease specialist at the University of Calgary in Alberta, Canada, treated 31 patients with the bacterial pills, curing all but one. Because the pills are less invasive than other techniques for treating the disease, they could make gut microbiome transplants available to more patients — including those who, for medical reasons, cannot tolerate an enema or tube from the nose to the small intestine. Louie had initially created the capsules when treating such a patient.

C. difficile often sets in after antibiotic use has disrupted a person’s normal balance of gut bacteria. A gut microbiome transplant using bacteria from the faeces of a healthy donor restores that balance, and can be highly effective against C. difficile, which is notoriously difficult to treat with antibiotics.

Gut reaction

The patients in Louie’s study each swallowed 24–34 freshly assembled capsules of bacteria, which were coated with gelatin to survive the stomach and reach the intestines. The team followed the patients’ progress for up to one year afterwards by sequencing the gut microbiome. They found  thatC. difficile had disappeared and bacteria asociated with a healthy gut microbiome, such asBacteroidesClostridium coccoidesClostridium leptumPrevotellaBifidobacteria and Desulfovibrio, increased in numbers.

“This pill idea really is a big advance,” says Colleen Kelly, a gastroenterologist at Brown University’s Alpert Medical School in Providence, Rhode Island, who performs faecal microbiome transplants using colonoscopy.

A pill made of bacteria grown in a laboratory rather than those extracted from donor faeces is a future possibility, and Louie says that he has been contacted by parties interested in commercializing his pill. He adds that his team is currently experimenting with freezing bacteria for C. difficile treatment.

However, economic barriers to such a synthetic pill are significant. Elaine Petrof, an infectious-disease expert at Queen’s University in Kingston, Ontario, has created RePOOPulate, a mix of 33 different types of bacteria grown in the lab to mimic the microbiome. Her team spent two years getting the equipment to grow the bacteria up and running, but the process is still expensive and the bacteria finicky. “Honestly, good luck to you,” she says to companies trying to commercialize the technology.

The high cost of producing bacteria in this way would be less of a barrier if the alternative were not so cheap. As Tom Moore, a physician and infectious-disease specialist in Wichita, Kansas, puts it: “It’ll be difficult to compete with the ready availability and very cheap costs of human poop.”





This text  is part of a book chapter:
Salvucci.2013. Crohn´s Disease within the Hologenome Paradigm, in “Crohn’s Disease: Classification, Diagnosis and Treatment Options”, Nova Publishers, 2013 (you can find the complete book here)

In 1990, Dr Erika von Mutius compared the rate of allergies in children of Democratic Germany and Federal Germany and she found that, contrary to their initial hypothesis, poor children with low sanitary conditions and rural life had fewer incidences of allergies. By those times, Dr Stachman who was working with hay fever, postulated that a previos viral infection in children could result in higher risk to develop allergies, but the results he found rejected this hypothesis. Population groups that have either been vaccinated or infected with mycobacteria (Bacillus Calmette-Guerin (BCG)) have shown to an association with a reduced risk to develop allergic disorders (Strachan, 1989). Recently, more works support the hypothesis of exposition to mild infections reduces the incidence of atopic diseases.

These researches lead to postulate the Hygiene hypothesis also called the “old friends hypothesis” that considers that the interaction in early life with different microorganisms (Bacteria, Virus, Eukarya) results in a less risk to develop allergies and atopic diseases.

Either by cell number or by genome size the microbiota outnumbers their host. The hologenome theory coined by Zilberg-Rosenberg and Rosenberg (2008) considers that the host and their microbiome constitute a unity, the holobiont. This superorganism is a result of cohabitation of different organism integrated as one, and could be considered a result of symbiopoiesis, or codevelopment of the host and symbiont (Rosenberg and Zilber-Rosenberg, 2011; Gilbert et al. 2010; Rohwer et al., 2002; Margulis and Foster, 1991).  The genetic contribution of the microbiome is more than 100000 genes that provide numerous trials not encoded in our genome (Dumas, 2011).

This evolutionary approach that considers any organism a result of integration with microorganisms has many implications and it is related to the Bioma Depletion Theory (a kind of enlargement of the “hygiene hypothesis”) that considers that human (and all mammals) and their microbiome evolved as a “superorganism” (Kinross et al., 2008; Rook, 2009). The immune system can be seen as an interface with their symbiotic organisms that have co-evolved more than a defense against invading organisms. The widely appreciated medical care in combination with technology, increased the occurence of allergic disorders, autoimmune diseases and left us an over-reactive immune response caused by a loss and separation of our partners, our microbiome that normally interact with our immune system (Figure 1) (Kau et al., 2011; Garn and Renz, 2007).

These partners involve not only the commensal bacteria, but also metazoans “parasites” and millions of virus. Bacteria comprising the microbiome have mobile elements that include plasmids, transposons, integrons, bacteriophages (Jones, 2010) that constitute the mobilome (Siefert, 2009). This genetic pool and the horizontal gene transfer within the microbiome is a key factor of the microbiome activity and constitute the dynamic response to the environment leading to the adaptation of the holobiont. It fuels the adaptive potential of the whole holobiont (Figure 1). The metabolism of microbiome and the host are intertwined constituting an integrated organism. In multicellular eukaryotes, transposition, genome reorganizations, retrovirus extrusion or insertion, etc. must be taking place in the germ line to result in a structural or metabolic change. Somatic cells have an intragenomic dynamics in response to environmental conditions.

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Figure 1. The superorganism or holobiont is the result of integration of pre-existing systems: Mobile elements or “mobilome” respond to the environmental factors with dynamic movement between genomes that constitutes a key mechanism for metabolic and structural changes on microbiome. The metabolism of microbiome and the host are intertwined constituting an integrated organism (holobiont). The medical care, use of antibiotics, technology and western way of life, resulted in a change and lost of our microbiome and an increased occurence of autoimmune and metabolic diseases that are related with an immune disbalance (Modified from Salvucci, 2011).

Vannier-Santos and Lenzi (2011) explain that taking into account that organisms identified as “parasites” are almost the 80% of known species and considering that all the theoretical explanation obtained are based on just a little part of the total organisms that exist (Windsor, 1998), we can refer to parasites as cohabitants since this close interaction drives the evolution and existence of the organisms (Vannier-Santos and Lenzi, 2011). Microbes and helmints that normally are understood as parasites have cohabited with their host and they are even greater than the host. If nature is a continuous battle bacteria and parasites should have won a long time ago. Considering that Life exists as a net, as a process (Maturana and Varela, 1999) it is possible to say that no organisms are a free-living specie sensu stricto.

The host and its symbiotic microbiota acts in cooperation (thus cooperation becomes a priority instead of competition). Even when Zilber-Rosenberg and Rosenberg, 2008 suggests that it should be considered a unit of selection in evolution and they remarks that the theory is in agreement with darwinism, the hologenome theory represent a holistic approach that considers each specie or organism as a result of an integration and this mechanism is observed at every level of nature: insertional activities of virus, bacterial, viral and archaeal DNA in eukaryotic genomes, endosymbiotic relationships and holobionts. This paradigm (like symbiogenesis of Merenchovzky and Margulis) contrasts with the observable facts in nature against the individualistic, selfish and economist conception of darwinism.

The hologenome theory and the holistic approaches like the concept of autopoiesis coined by Maturana and Varela (Varela et al., 1974) and Lynn Margulis` endosymbiotic theory (Margulis and Fester, 1991) are related in understanding the evolution of life as integrative processes.  The concept of autopoiesis considers a living system as a dynamic composite entity, a unity as a closed network of productions of components in a way that through interactions in composition and decomposition, the components: a) recursively constituted the same network of production that produced them, and b) specify the extension of the network and constitute operational boundaries that separate it as a dynamic unity in a space defined by elements of the kind of those that compose it (Maturana, 2002). The word autopoiesis connotes the organization of living systems as closed networks of molecular production. The endosymbiotic theory explains the emergence of organelles and nucleus of eukariotyc cells. These theoric frameworks and the hologenome theory explains that the existence of each organism is the consequence of integration of pre-existing organisms (or parts), but the result is more than the sum of the parts. Any organism is the result of an inherent property of autoorgnanization and autopiesis. The genome of each organism is the result of combination of bacterial, virus and eukaryotic DNA. Finally, any organism is the result of the interaction of their own genome with the genome of the organisms that co-evolved with it. In the case of mammals, the principal organism or “host” is the result of integration with their microbiota (constituting the holobiont), and their metabolisms were and are intertwined (as a “superorganism”) along evolution. (Vannier-Santos and Lenzi, 2011; Kau et al., 2009; Tilg and Kaser, 2011; Gazla and Carracedo, 2009; Zilber-Rosenberg and Rosenberg, 2008).

Microbial eukaryotes in the human gut have been studied primarily from a parasitological point of view and are generally considered to impact negatively on human health (Parfrey et al. 2011). Biome depletion theory could explain that these cohabitants were necessary to maintain the homeostasis of the superorganism or holobiont.

Nowadays, several diseases are considered the new epidemics. The incidence of a group of diseases have increased since the industrial era. These are related to a hyperreactive immune system and this unbalance is related to the separation of our partners along the last thousands years. The immune balance was maintained by the microbiota that humans have been losing with modern medicine, new technologies and changes in the way of life.

Autoimmune diseases like type 1 diabetes, artritis, lupus and inflammatory related diseases like infflamatory bowel disease (IBD), diabetes, asthma could be treated with a biome restoring process that could be done by probiotic administration. The genetic background necessary to develop any of these illnesses (intrinsic factors) is directly and closely related and influenced by the metabolism of microbiota (extrinsic factors) (Tilg and Kaser, 2011; Proal et al., 2009).

The importance of Bacteria on health was recognized along the last twenty years. It was observed the healthy status of people from different regions in where there was a high intake of fermented products. The benefits of different foods, that were known for centuries, leaves to the discover of different bacterial strains, mainly, Lactic Acid Bacteria that were postulated, after many studies, as probiotics (Fujimura et al., 2010).

Probiotics are defined today as ‘live microorganisms which, when administered in adequate amounts, confer a beneficial health effect on the host’. They could be bacterial cells like lactic acid bacteria or eukaryotic microorganisms like helminths. A reductionist perspective leads to the study of different strains that could restore or specifically get a benefit. There are several studies related to determine the mechanism and products involved in the benefit that could be ensured by the action of one bacteria strain (Fujimura et al., 2010; Dominguez Bello and Blaser, 2008).

The study of probiotics, since their beginning and nowadays, is directed to use an  specific strain that restores one symptom or disease. The hologenome theory considers us as a superorganism, added it with the biome depletion theory show us that what it is unbalanced is the entire immune system and the reasons of the increase of incidence and the probable therapies, would be analyzed taking account that we need to restore a whole microbiome and not search an specific strain for each disease. Of course, this is impossible because we are now, without those lost partners, a different holobiont. But, what we can do is to change our reductionist and incomplete view and research to know and understand the complete microbiome in each health/disease situation. And with this, try to figure out which are the accurate therapies.